6-Substituted 3-carbethoxyhydrazinopyridazine

ABSTRACT

6-SUBSTITUTED 3-CARBETHOXYHYDRAZINOPYRIDAZINES OF THE GENERAL FORMULA:   WHEREIN R1 and R2, which may be the same or different, represent a lower alkyl group containing from 1 to 6 carbon atoms, an allyl group, a 2-hydroxyethyl group or a 2-hydroxypropyl group, as well as the pharmaceutically acceptable salts thereof. Also a method of preparation. These compounds have anti-hypertensive activity.

United States Patent [1 1 Carpi et al.

[451 Dec. 9, 1975 6-SUBSTITUTED 3-CARBETHOXYHYDRAZINOPYRIDAZINE [75]Inventors: Carlo Carpi, Reggio Emilia; Luciano Dorigotti; GiorgioPifferi, both of Milan, all of Italy [73] Assignee: l.S.F. S.p.A.,Milan, Italy [22] Filed: Mar. 4, 1974 [21] Appl. No.1 447,523

[30] Foreign Application Priority Data Primary Examiner-Richard J.Gallagher Assistant Examiner-Anne Marie T. Tighe Attorney, Agent, orFirmStevens, Davis, Miller & Mosher ABSTRACT 6-substituted3-carbethoxyhydrazinopyridazines of the general formula:

R O NI-INHCOOC2H5 wherein R and R which may be the same or different,represent a lower alkyl group containing from I to 6 carbon atoms, anally! group, a 2hydroxyethyl group or a 2-hydroxypropyl group, as wellas the pharmaceutically acceptable salts thereof. Also a method ofpreparation. These compounds have antihypertensive activity.

6 Claims, No Drawings 6-SUBSTITUTED 3-CARBETHOXYHYDRAZINOPYRIDAZINE Theevaluation of the acute toxicity was carried out in the mouseadministering the products by the intraperitoneal route at 6 differentdosage levels. The approximate LD, was determined thereafter.

TABLE 'ED,.,= dose producing a 20% fall in pressure compared to thebasal value.

The present invention relates to new derivatives of pyridazinepossessing remarkable pharmacodynamic properties. More particularly, theinvention relates to new o-substituted 3'carbethoxyhydrazinopyridazinesof the general formula: V

- NHNH-COOC H or with organic acids, such as acetic, succinic, benzoic,

p-toluensulphonic acid etc.

It is known that some derivatives of 6-substituted 3-hydrazinopyridazine possess remarkable anti-hypertensive activity.However, the therapeutic applications of said drugs are limited by thefact that they cause tachy cardia, headache, vertigo, etc., owing to therapidity with which the hypotensive effect develops. Furthermore,repeated daily administrations are necessary to maintain the desiredeffect.

It has now been discovered that in the class of derivatives of formula(I) where a Z-carbethoxyhydrazinic group is contained in the molecule,the anti-hypertensive effect develops with a slow progression and isdefinitely more prolonged compared to similar drugs such as Hydralazineand Binazin.

Some illustrative results obtained in the renal hypertensive awaken rataccording to the method of A. Grollman (Proc. Soc. Exptl. Biol. Med.,57, 102,1944) are given in Table l. The products were administeredorally'to groups of 4 rats for each dosage level. The ar terial pressurewas measured by bloodless method immediately before and at the lst, 3rd,5th, 7th, 12th, 24th, 36th, 48th and 60th hour after administration.

The results listed in the above Table show that the compounds of thepresent invention display low toxicity, high activity, and possess thecharacteristic of a more gradual development of the hypotensive effect,as proved by the value of maximum effect appearance times. The highervalues of the half effect time show furthermore the really exceptionalduration of the hypotensive effect developed in the experimentallyhypertensive animal.

The compounds of the invention and pharmaceutically acceptable saltsthereof are useful as pharmaceuticals and are characterized by activityas antihypertensive agents.

These compounds can be used in the form of conventional pharmaceuticalpreparations; for example, the aforesaid compounds can be mixed withconventional organic or inorganic, inert pharmaceutical carrierssuitable for parenteral or enteral administration such as, for example,water, gelatin, lactose, starch, magnesium stearate, talc, vegetableoil, gums, polyalkylene glycols, vaseline or the like. They can beadministered in conventional pharmaceutical forms, e.g. solid forms, forexample, tablets, dragees, capsules and the like; or in liquid forms,for example, injectable solutions, suspensions or emulsions. Moreover,the pharmaceutical compositions containing compounds of this inventioncan be subjected to conventional pharmaceutical expedients such assterilisation and can contain conventional pharmaceutical excipientssuch as preservatives, stabilizing agents, wetting agents, emulsifyingagents, salts for the adjustment of osmotic pressure or buffers. Thecompositions can also contain other therapeutically active materials.

A suitable pharmaceutical dosage unit can contain from about I to 5 mgdaily of the aforesaid compounds and due to their long-lasting effectthis dosage can be also administered in a single daily dose.

The present invention furthermore relates to a process for thepreparation of the new pyridazine derivatives of formula (I), comprisingthe reaction between a compound of the formula:

wherein R and R have the above meaning and X rep resents a chlorine orbromine atom and monocarbethoxyhydrazine:

H,N-NHCOOC,H, (111) Derivatives of formula (1]) used as startingmaterials are known, as is monocarbethoxyhydrazine (Ill). The compoundsof formula (ll) are warmed up with two equivalents ofmonocarbethoxyhydrazine preferably in the absence of solvents and at atemperature ranging between 140l60C. The excess monocarbethoxyhydrazineserves to help the reaction, blocking the hydrochloric acid which formsduring the condensation with the compounds of formula (11). The durationof the reaction is not critical but the operation is preferably car riedout during a short period of time ranging from about a half an hour toabout 1 hour of heating. When heating is over, the reaction mass istaken up with a protic solvent, preferably aqueous or alcoholic, and thebase of formula (I) is made free of alkalinization with suitable basicagents such as bicarbonates, carbonates, or alcoholates of alkalimetals. The isolation of the final product is carried out byprecipitation, concentration or extraction according to the usualmethods, and successive purification can be carried out by conventionalcrystallization or chromatography.

The following Examples, which are not limitative, serve to illustratethe present invention.

EXAMPLE 1 3-( Z-Carbethoxyhydrazino )-6-dimethylaminopyridazinehydrochloride A mixture of 1.57 g (0.01 moles)3-chloro-6-dimethylaminopyridazine and 2.08 g (0.02 moles)monocarbethoxyhydrazine is warmed up for half an hour at 160C. Theresulting mixture is cooled, water added thereto, the solid whichseparates filtered away and the filtrate neutralized with NaHCO, until afinal pH 7. The mixture is then extracted with cloroform, the organicextract dried over sodium sulphate and the solvent evaporated. Theresidual oil is purified by chromatography on silica gel, eluting with amixture of chloroforimmethanol 8.5:1.5. The unitary fractions on thinlayer chromatography with the same Rf are collected together, evaporatedand the residue treated while warm with ethyl ether, and the residuefiltered off. By addition of hydrogen chloride to the filtrate,3-(2-carbethoxyhydrazino )-6-dimethylaminopyridazine hydrochlorideprecipitates with good yields melting at 2l52l7C (with dec). l.R.Spectrum (mineral oil, cm"): 3200 (NH), 1715 (C==O carbamate), 1595(pyridazinic ring), 840 (two ortho-aromatic hydrogens).

Analysis: Calculated for C,H,,N,O,.HC1: C, 41.30; H, 6.16; N, 26.76; C1,13.55. Found: C, 41.59; H, 6.20; N, 26.77, Cl, 13.29.

EXAMPLE 2 3-( Z-Carbethoxyhydrazino )-6-[ N-( Z-hydroxyethylmethylaminol-pyridazine A mixture of 1.87 g (0.01 moles)3-ch1oro-6-[N-(2- hydroxyethyl)-methylaminol-pyridazine and 2.08 g (0.02moles) monocarbethoxyhydrazine is warmed up to 155C and kept at thistemperature for half an hour. The product is cooled and dissolved inwater, alkalinized by addition of solid potassium carbonate and theaqueous solution saturated by adding sodium chloride.

A flocky precipitate separates which is subsequently collected byfiltration and crystallized from ethanol, to give with good yields3-(Z-carbethoxyhydrazino)-6-[N- (Z-hydroxyethyl) methylaminol-pyridazinemelting at l31-l33C. 1.R. Spectrum (mineral oil, cm); 3320-3080 (OH andNH), 1715 (C=O carbamate), 1500 (pyridazinic ring), 840 (two orthoaromatic hydrogens).

Analysis: Calculated for C H N O C, 47.05; H, 6.71; N, 27.43. Found C,46.89; H, 6.81; N, 27.74.

EXAMPLE 3 3-( 2-Carbethoxyhydrazino)-6-[N-(2-hydroxypropyl)-methylamino1-pyridazine A mixture of 6 g (0.029 moles) 3-chloro-6-[N-(2-hydroxypropyl)-methylamino]-pyridazine and 6.2 g (0.069 moles)monocarbethoxyhydrazine is warmed up to 145C and kept at thistemperature for 1 hour. After cooling, the residue is taken up in waterand the solution extracted with chloroform. The aqueous phase is cooledand treated with potassicurn carbonate until complete precipitation. Theprecipitation is collected and purified by crystallization from ethanolto give with good yields 3-(2-carbethoxyhydrazino)-6-[N-(2-hydroxypropyl)-methy1amino]-pyridazine melting at 150-152C.

Analysis: Calculated for C H,,N,O,: C, 49.06; H, 7.11; N, 26.00. FoundC, 49.15; H, 7.50; N, 26.04.

EXAMPLE 4 3-(Z-Carbethoxyhydrazino)-6-[di-(2-hydroxyethy1)-aminol-pyridazine hydrochloride A mixture of 4.34 g (0.02 moles)3-chloro-6-bis-(2- hydroxyethyl)-aminopyridazine and 4.16 g (0.04 moles)monocarbethoxyhydrazine is warmed up to 140C and kept at suchtemperature for 1 hour. The mixture is cooled, methanol added theretountil solution, and neutralized with a methanol solution of sodiummethoxide to pH 7. The solvent is evaporated and the residual oilpurified by chromatography on silica gel column, eluting with a mixtureof chloroformzmethanol :15. The unitary fractions on thin layerchromatography with the same Rf are collected together, evaporated andthe residue, taken up with acetone, is acidified with hydrogen chloride.Good yields of 3-(2- carbethoxyhydrazino)-6-[di-(2-hydroxyethyl)-amino]-pyridazine hydrochloride melting at 162-l65C (with dec.) are obtained.

l.R. Spectrum (mineral oil, cm): 3450-3200 (OH and NH), 1710 (C=Ocarbamate) 1595 (pyridazinic ring). 840 (two ortho aromatic hydrogens).

Calculated for C,,H,,N,O .HCI: C, 41.06; H, 6.26; CI, 11.01; N, 21.76.Found C, 40.90; H, 5.90; Cl, 10.50; N, 22.41.

EXAMPLE 5 3 -(2-Carbethoxyhydrazino)-6-c1ial1ylaminopyridazine A mixtureof 4.18 g (0.02 moles) 3-ch1oro-6-diallylaminopyridazine and 4.16 g(0.04 moles) monocarbethoxyhydrazine is warmed up to C and kept at thistemperature for 1 hour. The mixture is taken up with cool water andsodium carbonate is added until neutral pH. it is then extracted withmethylene chloride, the organic extracts collected together, dried oversodium sulphate and concentrated. The residual oil is purified bychromatography on silica gel column, eluting with a mixture ofchloroform-methanol 9.5:0.5. The unitary fractions on thin layerchromatography with the same Rf are collected together; the solvent iseliminated by evaporation and a yellow oil formed by 3-( 2-carbethoxyhydrazino)-6-diallylaminopyridazine is obtained.

[.R. Spectrum (mineral oil, cm); 3350-3100 (NH), 1715 (C=O carbamate),1645 (Cl-[=CH,), 830-825 (two ortho aromatic hydrogens).

Analysis: Calculated for c, H,,N 0,: C, 56.30; H, 6.90; N, 25.25. FoundC, 56.01; H, 6.80; N, 25.48.

What is claimed is:

l. A compound of the formula:

m NHNH-COOC2H5 V (1) 2

1. A COMPOUND OF THE FORMULA: 2.3-(2-Carbethoxyhydrazino)-6-dimethylaminopyridazine and itspharmaceutically acceptable salts. 3.3-(2-Carbethoxyhydrazino)-6-(N-(2-hydroxyethyl)methyl-amino)-pyridazineand its pharmaceutically acceptable salts. 4.3-(2-Carbethoxyhydrazino)-6-(N-(2-hydroxypropyl)methyl-amino)-pyridazineand its pharmaceutically acceptable salts. 5.3-(2-Carbethoxyhydrazino)-6-(di-(2-hydroxyethyl)-amino)-pyridazine andits pharmaceutically acceptable salts. 6.3-(2-Carbethoxyhydrazino)-6-diallylaminopyridazine and itspharmaceutically acceptable salts.